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Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung.

ABSTRACT: Cancer metastasis is responsible for the clear majority of cancer-related deaths. Survival and expansion of cancer cells at secondary sites requires that these premetastatic microenvironments be primed by primary tumor cells and their secreted factors. Efforts to date have been limited by immune-deficient in vivo models and/or the need for finely-tuned analysis time points that reduce contributions from early-disseminating cancer cells. In this regard, we developed a tumor cell-free syngeneic breast cancer model for characterizing tumor cell secretome-mediated reprogramming of premetastatic tissues. We demonstrate that secretomes from metastatic breast cancer cells differentially regulate the lung and brain, promoting a tumor-supportive lung microenvironment with both elevated CD73 expression and decreased TNF? expression. Using in vitro models of CD73-positive mesenchymal stem cells (MSCs) and macrophages/monocytes, we tested whether MSCs can mediate anti-inflammatory effects of metastatic breast cancer cells. Notably, conditioned media from metastatic Py230 cells reprogrammed the secretomes of MSCs toward an anti-inflammatory state. Mining transcriptome data from Py8119 and Py230 cells revealed a lipocalin 2 (LCN2) axis that is selectively expressed in the metastatic Py230 cells, predicts poor breast cancer patient survival and is elevated in circulating serum of mice chronically treated with conditioned media from Py230 cells. Taken together, these results establish the utility of an immune-competent tumor cell-free model for characterizing the mechanisms of breast cancer cell priming of the premetastatic niche, demonstrate that MSCs can mediate the anti-inflammatory effects of metastatic breast cancer cells and substantiate LCN2 as a promising therapeutic target for blocking breast cancer progression.

SUBMITTER: Meade KJ

PROVIDER: S-EPMC6508963 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung.

Meade Kayla J KJ Sanchez Francesca F Aguayo Analine A Nadales Nathalie N Hamalian Sarkis G SG Uhlendorf Toni L TL Banner Lisa R LR Kelber Jonathan A JA

Oncotarget 20190430 32

Cancer metastasis is responsible for the clear majority of cancer-related deaths. Survival and expansion of cancer cells at secondary sites requires that these premetastatic microenvironments be primed by primary tumor cells and their secreted factors. Efforts to date have been limited by immune-deficient <i>in vivo</i> models and/or the need for finely-tuned analysis time points that reduce contributions from early-disseminating cancer cells. In this regard, we developed a tumor cell-free synge ...[more]

PMID: 31105883

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Project description:BackgroundThe secretomes of mesenchymal stem cells (MSCs) have great therapeutic potential and thereby their efficient delivery into the target site is of particular interest. Here, we propose a new strategy of hMSCs-derived secretomes delivery for advanced wound healing upon harnessing the working principle of extracellular matrix (ECM)-growth factors interaction in vivo.MethodsWe prepared an alginate hydrogel based wound patch, where it contains both human MSC-derived secretomes and ECM. The ECM was obtained from the decellularization of in vitro cultured human lung fibroblasts. The alginate solution was blended with ECM suspension, crosslinked, air-dried, then rehydrated with the secretomes contained in the concentrated conditioned media (CCM) as a highly saturated form of conditioned media (CM). We tested four different groups, with or without the ECM to investigate not only the role of ECM but the therapeutic effect of secretomes.ResultsThe secretomes reserved many, diverse bioactive factors, such as VEGF, HGF, IGFBPs, IL-6, and IL-8. Alginate/ECM/CCM (AEC) patch could hold significantly larger amount of secretomes and release them longer than the other groups. Our AEC patch was the most effective in stimulating not only cell migration and proliferation but the collagen synthesis of dermal fibroblasts in vitro. Moreover, the AEC patch-treated full-thickness skin wounds disclosed significantly better wound healing indications: cell recruitment, neovascularization, epidermis thickness, keratinocyte migration, and mature collagen deposition, as assessed via histology (H&E, Herovici staining) and immunofluorescence, respectively. In particular, our AEC patch enabled a phenotype shift of myofibroblast into fibroblast over time and led to mature blood vessel formation at 14 day.ConclusionsWe believe that ECM certainly contributed to generate a secretomes-enriched milieu via ECM-secretomes interactions and thereby such secretomes could be delivered more efficiently, exerting significant therapeutic impact either individually or collectively during wound healing process.

Project description:ObjectivesEvaluate the efficacy of interventions to improve symptoms for ICU surrogates at highest risk of developing psychologic distress: those facing end-of-life care decisions.Data sourcesMEDLINE, CINAHL, PsycInfo, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched through April 16, 2022.Study selectionFollowing an a priori protocol, randomized trials of interventions delivered to surrogates of adult ICU patients who died or had high likelihood of mortality evaluating surrogate symptoms were identified.Data extractionTwo reviewers performed screening and data extraction and assessed risk of bias (Cochrane Risk of Bias [RoB] 2 tool). Trials were eligible for meta-analysis if group mean symptom scores were provided at 3 or 6 months. Pooled effects were estimated using a random effects model. Heterogeneity was assessed (Cochrane Q, I2 ). Certainty of evidence was assessed (Grading of Recommendations Assessment, Development and Evaluation).Data synthesisOf 1,660 records, 10 trials met inclusion criteria representing 3,824 surrogates; eight were included in the meta-analysis. Overall RoB was rated Some Concerns. Most ( n = 8) interventions focused on improving communication and enhancing psychologic support in the ICU. All trials measured anxiety, depression, and posttraumatic stress. Significant improvement was seen at 3 months (depression, mean difference [MD], -0.68; 95% CI, -1.14 to -0.22, moderate certainty; posttraumatic stress, standardized MD, -0.25; 95% CI, -0.49 to -0.01, very low certainty) and 6 months (anxiety, MD, -0.70; 95% CI, -1.18 to -0.22, moderate certainty). Sensitivity analyses suggest significant findings may be unstable. Subgroup analyses demonstrated differences in effect by trial location, interventionist, and intervention dose.ConclusionsCommunication and psychological support interventions in the ICU yielded small but significant improvement in psychological symptoms with moderate to very low certainty evidence in a prognostically-enriched sample of ICU surrogates facing end-of-life care decisions. A new approach to interventions that extend beyond the ICU may be needed.

Dataset Information

Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung.

Publications

Secretomes from metastatic breast cancer cells, enriched for a prognostically unfavorable LCN2 axis, induce anti-inflammatory MSC actions and a tumor-supportive premetastatic lung.

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